Acute and Chronic Effects of Ethanol on Fluid Transport in the Human Small Intestine

Vol. 72, No.6 Printed in U.S A.

72:1280-1286, 1977 Copyright © 1977 by the American Gastroenterological Association

GASTROENTEROLOGY

ACUTE AND CHRONIC EFFECTS OF ETHANOL ON FLUID TRANSPORT IN THE HUMAN SMALL INTESTINE HAGOP

S.

MEKHJIAN, M.D., AND EUGENE

S.

MAY, M.D.

Division of Gastroenterology, College of Medicine, The Ohio State University, Columbus, Ohio

The effect of acute and chronic administration of ethanol on jejunal and ileal water and electrolyte transport was studied in healthy volunteers by the triple lumen intestinal perfusion technique. The acute perfusion of a glucose-free electrolyte solution containing 2 to 10 g per 100 ml of ethanol in the jejunum or ileum did not cause any significant alterations of sodium or water transport. In contrast, the administration of a folate-deficient diet and ethanol for 2 weeks produced a marked reduction in sodium and water absorption or a small net secretion (control, mean ± SE: H 2 0 = 0.91 ± 0.06 ml per min, Na = 130 ± 8/LEq per min per 30 cm of intestine versus H 2 0 = -0.13 ± 0.14 ml per min, Na = -20 ± 29 /LEq per min per 30 cm, P < 0.001). These changes were not accompanied by a reduction in serum folate levels. The administration of ethanol with a folate-supplemented diet also produced significant but less pronounced changes in sodium and water transport (control: H 2 0 = 1.33 ± 0.2 ml per min, Na = 185 ± 34 /LEq per min per 30 cm of intestine versus H 2 0 = 0.48 ± 0.17 ml per min, Na = 65 ± 16 /LEq per min per 30 cm of intestine, P < 0.05). From this study it appears that the diarrhea seen in chronic alcoholics can be explained in part by the effect of ethanol on intestinal sodium transport, without any accompanying changes in serum folate levels. Diarrhea or malabsorption of water and electrolytes! is frequently associated with chronic alcoholism. 2 , 3 Ethanol produces a reduction in the short circuit current in the frog's skin, 4 reduces the potential difference in the human stomach5 , 6 and the hamster jejunum, as well as reducing the net absorption of water in vitro 7,8 and in vivo. 9 Green et al. have also demonstrated that ethanol stimulates adenyl cyclase activity in the rat and human intestinal mucosa in vitro with an associated increese in cyclic 3' ,5' -adenosine monophosphate (cAMP).!O All of the above observations suggest that ethanol might either interfere with the active transport of sodium or induce secretion of water and electrolytes in the gastrointestinal tract, thereby contributing to the diarrhea observed in patients with chronic alcoholism. There are no available studies in man that have examined the effect of various concentrations of ethanol on the human intestinal water and electrolyte transport. Furthermore, the chronic effects of ethanol on human intestinal absorption have only been examined

in chronic alcoholics with uncontrolled dietary intake,3 or after the prolonged intake of ethanol and folatedeficient diet in reformed alcoholics. 11 The present study was undertaken, therefore, to examine the effect of acute and chronic (2 weeks) administration of ethanol on jejunal and ileal water and electrolyte transport in healthy human volunteers while taking nutritionally adequate diets. The results indicate that the acute intestinal perfusion of ethanol does not produce any significant alterations in human intestinal sodium transport. In contrast, the administration of ethanol for 2 weeks produced either a diminution of absorption or a small net secretion of sodium and water by the jejunum and ileum. A folate-deficient diet seemed to augment the abnormalities of transport without an accompanying decrease in serum folate levels. Methods

Perfusion procedure. Healthy male and female subjects between the ages of 21 and 35 were admitted to the Clinical Research Center and studied by the triple lumen perfusion Received June 30, 1976. Accepted December 15, 1976 technique!2 after being fully informed of the experimental This paper was presented in part at the American Federation for procedure and signing an informed consent. The small bowel Clinical Research Meeting, Chicago, November 2, 1974. was intubated with the triple lumen tube described above, and Address requests for reprints to: Hagop S. Mekhjian, M.D., Divi- the perfusion port was positioned at the ligament of Treitz sion of Gastroenterology, N-937 University Hospital, The Ohio State under fluoroscopic control. Two ports 15 and 30 cm more University, 410 West 10th Avenue, Columbus, Ohio 43210. distally placed served as sampling sites during the perfusion. This study was supported in part by Grant 5R01AA00202 from the The control perfusates contained a nonabsorable marker, polyNational Institute on Alcohol, Clinical Research Center Grant RR-34 ethylene glycol (PEG), 5 g per liter, and sodium 145, potasfrom the National Institutes of Health, and Project Number 7508 sium 5, chloride 140, and bicarbonate 10 mEq per liter (pH 8.2) from the Bremer Foundation. in some experiments 2 mEq per liter of calcium was added to Mr. Anton Ailabouni provided technical assistance and Ms. Betty the perfusates. These solutions contained sodium 145, potasDaniel provided valuable secretarial help. sium 5, chloride 147 mEq per liter, and bicarbonate was omit1280

June 1977

ETHANOL AND INTESTINAL SODIUM TRANSPORT

ted, thus lowering the pH of these perfusates to 6.9. The osmolality of all of the control solutions was 290 milliosmoles per kg. Solutions were penused at 10 ml per min from the most proximal port by peristaltic perfusion pump. Because glucose transport can influence bulk water flow, we omitted it from our perfusates. This enabled us to study the effect of ethanol on sodium absorption per se. The opening 15 cm distal to the perfusion port was sampled at the rate of 0.5 to 1.0 ml per min, and the distal sampling site was left open to drain by siphonage. New water and electrolyte movements in the 30-cm test segment (between the two collecting sites) were determined under steady state conditions. The time required to achieve steady state varied from 30 to 90 min and usually was 60 min. After the establishment of steady state condition, at least four and usually six sequential 15-min samples were analyzed. The collection periods were "staggered" before analysis. 13 The establishment of steady state conditions was later verified by the analysis of PEG and experiments in which satisfactory steady state had not been established were discarded. After the determination of normal absorption from physiological solutions, the subjects were perfused with solutions containing alcohol in concentrations of 10, 4, 3, and 2 g per 100 mI. The test solutions were prepared by the addition of ethanol to the control solutions. The osmolality of the test solutions were 2346, 1970, 970, and 738 milliosmoles per kg for the 10, 4,3, and 2 g per 100 ml alcoholic solutions, respectively (pH 8.3). In 8 subjects 24Na was added to the perfusate during the perfusion of both the control and alcohol solutions to monitor the unidirectional movements of this cation. 14 When the ileum was being perfused, the perfusion tube was allowed to advance 225 cm from the mouth overnight and the perfusion carried out the next day was similar to the jejunal perfusions. Experimental design. Water and electrolyte absorption were measured in each subject during the perfusion of the electrolyte solution and compared with the absorption during the perfusion of alcoholic solutions of varying concentrations. Each perfusion was separated by an interval of at least 60 min to achieve a new steady state with the solution. Only one concentration of alcohol was perfused in each subject and the control solutions were always perfused first. During the perfusion of alcoholic solutions blood was drawn at 15-min intervals for the determinations of blood alcohol levels. Nineteenjejunal and three ileal perfusions were done in as many subjects to test the acute effects of ethanol on small intestinal water and electrolyte transport. In 13 normal nonalcoholic subjects the effect of a 2-week intake of ethanol on intestinal transport was studied. At the beginning of each study jejunal or ileal absorption was measured as described above. After the intestinal perfusion the subjects were put on an experimental diet, similar to the diets used by Lieber et al. 15 The diet contained 35% ofthe calories as fat, 18% as protein, 11 % as carbohydrate, and 36% as ethanol. Four subjects were studied while taking this diet and vitamin supplements included folic acid by mouth. The remaining 9 subjects took a diet made folate deficient by the triple boiling method. I6 Careful attention was paid to the patients' caloric intake and daily adjustments in caloric intake were made to maintain their weight. Periodic blood tests were done to monitor the patients' hepatic, pancreatic, and hematopoietic function only for the safety of the subjects being studied. Serum folate levels were determined in all subjects at the beginning and at the end of the 2-week period. At the end of the 2-week period the patients were intubated again, their intestines were perfused after an overnight fast, and intestinal absorption of water and electrolytes were measured in an identical fashion as before the intake of ethanol. Thus, each patient served as his own control and all perfusions were done at a time when the blood ethanol levels were zero.

1281

Analytic methods . Sodium and potassium were measured by flame photometry, chloride electrotitremetrically, and bicarbonate manometrically. PEG was measured turbidimetrically at 650 mu by the method of Hyden. 17 The presence of 1 to 10 g per 100 ml of ethanol in the solutions did not alter the PEG determinations. 24N a was counted in an auto gamma spectrometer. Blood and intestinal fluid ethanol measurments were done by gas liquid chromatography.18 Serum folic acid levels were determined by microbiological assay.19 Calculations and statistical analysis . Net absorption ofwater (milliliters per minute) and electrolytes
Results Effect of ethanol perfusion on jejunal and electrolyte transport. The concentrations of ethanol achieved in the test segment varied with the concentrations in the perfusate. It was impossible, however, to maintain high concentrations of ethanol in the test segment (table 1). The perfusion of the 10, 4, 3, and 2% solution of ethanol into the proximal small intestine did not cause any significant reduction in water and electrolyte absorption (P > 0.05) when compared to their control levels (fig. 1, table 2). In the 10 subjects in whom unidirectional movements of sodium were measured, ethanol did not cause any significant changes in transport (P > 0.05), (control, mean ± BE, insorption 739 ± 67, exsorption 557 ± 48, versus insorption 685 ± 94, exsorption 521 ± 55 p,Eq per min per 30 cm). The somewhat lower absorption from the control solution in subjects 12 to 19 (fig. 1, table 2) probably is attributable to the lack of bicarbonate in the perfusates. 21 The acute perfusion of 2% ethanol did not cause any significant changes in absorption in the ileum (P > 0.05, table 2). The absorption and the peak blood level of ethanol was greater from the more concentrated ethanolic solutions, but these did not seem to correlate with the absorption of water and electrolytes (tables 1 and 2). Effect of chronic ethanol intake on absorption of water and electrolytes. There was about a 50% reduction in absorption of sodium and water in the 4 subjects who had taken ethanol for 2 weeks together with a diet rich in vitamins (P < 0.05). No net secretion was observed. The 6 subjects who had received ethanol for the same length of time but who were on a folate-deficient diet, a more pronounced reduction in absorption or a small net secretion in water and sodium occurred at the end of the 2-week period (figure 2, table 3). The changes produced by ethanol are significantly different from the control period (P < 0.0001). The reduction in absorption is also significantly greater in the subjects who were on a folate-deficient diet when compared to the subjects who were on a folate-supplemented diet (P < 0.05). The

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MEKHJIAN AND MAY TABLE

Vol. 72, No.6

1. Mean concentrations" and mean peak blood levels of ethanol during acute perfus ions Mean concenPeak blood Mean blood Proximal site Distal site tration in test level level segment

Ethanol infusion

Study

g/lOO ml

g/lOO ml

1-4 5-10 11-16 17-19 20-22 (ileum)

10 4 3 2 2

2.14 1.23 0.72 0.69 1.80

± ± ± ± ±

g/lOO ml

0.49 0.2 0.05 0.05 0.2

0.75 0.56 0.32 0.40 0.56

± ± ± ± ±

0.29 0.1 0.03 0.04 0.1

g/lOO ml

mg/lOO ml

-ng/lOO ml

1.45 0.90 0.52 0.55 1.18

133 51 53 81 NDb

105 ± 23 34 ± 9 38 ± 9 61 ± 10 ND

Mean absorption mg/30 em/min

867 464 310 372 530

± ± ± ± ±

170 112 44 50 11

" Mean ± SE. ND, not determined.

b

IOollOOml

I.

CONTROL

40/100ml CONTROL

ETHANOL

30/100ml

ETHANOL

CONTROL

ETHANOL

.uEq Imin/30cm

E u

..,o...... c:

E ......

i!r

z~ o

200

t

II::

g ID

ex

~ i5 o C/l

100

I11111

FIG. 1. The net jejunal absorption of sodium (microequivalent per minute per 30 em) from a control electrolyte solution and from electrolyte solutions containing 10, 4, or 3 g per 100 ml of ethanol. Shown are (mean ± SE) the results from 16 studies. Ethanol perfusion did not cause any significant alteration of sodium transport (P > 0.05). The somewhat lower absorption observed in the experiments done with 3% solutions of ethanol can be explained by the lack of bicarbonate in these perfusates (see text also). TABLE

Acute studies

Ethanol concentration

2. Effect of acute ethanol perfusion on water and electrolyte transport in the human small intestine" Net transport of water (mIimin) and electrolytes (ILEq/min) per 30 em of intestine

Absorption after ethanol intake

Absorption before ethanol intake Na

H 20

K

HCO,

Cl

Na

H 20

K

Cl

HCO,

g/lOO ml

1-4 5-10 11-16 b

17-19 b 20-22 (ileum)

10 4 3 2 2

1.79 1.97 1.15 1.1 0.86

± ± ± ± ±

0.4 0.5 0.1 0.2 0.2

250 232 142 174 123

± ± ± ± ±

62 61 11 47 23

9 12 8 6.5 4

± ± ± ± ±

1 4 2 2 0.6

207 262 204 168 136

± ± ± ± ±

41 58 33 56 20

30 ± 1 16 ± 2 NDc ND -14 ± 21

1.6 2.0 1.1 0.96 0.70

± ± ± ± ±

0.5 0.6 0.3 0.1 0.2

236 241 180 130 116

± ± ± ± ±

89 82 36 20 3

9 ± 1 10 ± 2 8 ± 1 6 ± 3 4±4

164 198 182 186 148

± ± ± ± ±

26 2 33 27 32

16 ± 5 12 ± 3

ND ND

-19 ± 22

" Values are mean ± SE. b Bicarbonate omitted from perfusion (see text). eND, not determined.

changes in chloride and bicarbonate transport (whenever measured) were similar to the alterations in sodium transport. The changes in potassium transport were not satistically significant (P > 0.05). In the 3 subjects in whom ileal absorption was measured after a

2-week period of intake of ethanol and a folate-deficient diet, there was a significant reduction in the net transport of water and electrolytes (P < 0.05, table 3). The fasting serum folate levels were normal in all patients at the beginning and at the end of the 2 weeks

June 1977

ETHANOL AND INTESTINAL SODIUM TRANSPORT

of experimental diet in both the folate-supplemented or folate-deficient diet group (table 4). In neither group there was a significant reduction in the serum folate levels at the end of the 2 weeks (P > 0.05). Discussion During the perfusion of 2, 3, 4, and 10 g per 100 ml solutions of ethanol into the jejunum, a similar rapid fall in the intraluminal ethanol concentrations occurred. Thus it was difficult to maintain very high concentrations of ethanol in the intestinal lumen. The highest concentrations of ethanol that could be maintained along a 30-cm segment of jejunum was 1.45 g per 100 ml (subjects 1 to 4, table 1). It should be pointed out that we might have been able to maintain the very high concentrations of ethanol in the intestine by using an occluding balloon22 and a shorter test segment. We elected not to do this because our intent was to stimulate as much as possible the conditions existing in the intestinal tract of the alcoholic patient. In this respect the triple lumen tube is more suitable as a method of measurement of intestinal absorption. These observations indicate that even with continuous perfusing of ethanol very high concentrations of ethanol are present WATER

A.

CONTROL

Z

ml

130cm

SODIUM CONTROl..

ETHANOL

ETHANOL

130cm

,uEq

0

Ii: ~

(/)

CD


mllmln/30cm

1 (/) CD

1.0

100

,uEq/mln/30cm

100


FIG. 2. The net jejunal absorption of sodium (microequivalents per minute per 30 cm) and water (milliliters per minute per 30 cm) before (control) and after a 2-week intake of ethanol and a folate-supplemented diet (A) or a folate-deficient diet (B). There is a significant reduction in absorption in group A but a more marked alteration in transport (net secretion) is seen in group B at the end of 2 weeks.

1283

in the human intestine only transiently, suggesting that any acute effects of ethanol on intestinal function produced by very high concentrations may have little relevance to disturbances of intestinal function observed in the alcoholic patient. The present studies also indicate that the acute perfusion of ethanol does not produce any significant changes in water and electrolyte transport in the human jejunum or ileum. Dinda et al. 7 have shown that a 2% solution of ethanol produces significant reduction of glucose and water absorption in the hamster jejunum in vitro. Fox et al. 9 have recently shown similar changes with a 4.8% solution of ethanol in the hamster jejunum in vivo. Although these animal experiments may seem at variance with the present human studies, there are important differences in the experimental design in addition to differences of the species studied. Because ethanol is primarily metabolized by the liver23 much higher luminal and intracellular concentrations of ethanol can be expected during in vitro experiments. Inasmuch as glucose was included in the perfusates in the hamster experiments one cannot separate the effects of ethanol on glucose transport, bulk water flow, and sodium transport. During our experiments the perfusates did not contain glucose and the highest mean luminal concentration of ethanol was 1.45 g per 100 ml, which did not produce any changes in sodium transport. These results are in agreement with pervious work by Beck et al. 8 which showed that at concentrations of ethanol below 2% isosmolar absorption of water and glucose continues. The abnormalities of absorption reported by Fox et al. 9 were produced by a 4.8% solution of ethanol. The relevance of these latter observations to human beings can be questioned in view of the much lower luminal concentrations of ethanol noted in our experiments. During the acute perfusions our solutions were definitely hyperosmolar. Of greater importance, however, is the osmolarity in the test segment. In spite of rapid modification of the infusate the osmolarity in the test segment ranged from 388 to 586 milliosmoles per kg and normal water absorption occurred from these solutions. Absorption of water from hyperosmolar solutions of glucose,24 450 milliosmoles of formamide, 8 1. 8 % of ethanol in Krebs-Ringer bicarbonate (approximately 600 milliosmolar),8 and up to 891 milliosmolar solutions of urea25 has been observed. In the case of the solutions mentioned above the linear relationship between increased osmolarity and reduction in water absorption is not present. 25 It is likely that the very rapid absorption of ethanol from hypertonic solutions contributed to water absorption. This can be explained by the serial membrane theory for the absorptive cell as proposed by Curran. 26 In addition to the osmolality of our perfusates, the factors that might have influenced absorption include the reflection coefficient of ethanol, the activity coefficient of sodium in alcoholic solutions, and the pharmacological effects of ethanol. 27, 28 Because no alteration of transport was observed, however, it can be assumed that the combined effect of all of these factors was negligible under our experimental conditions.

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MEKHJIAN AND MAY TABLE

Vol. 72, No.6

3. Effect of 2 weeks of ethanol intake on water and electrolyte transport in the human small intestine a Net transport of water (ml!min) and electrolytes (J.'Eq/min) per 30 cm of intestine

Study·

Diet A 1 2 3 4 Mean ± Diet B 5 6 7 8 9 10 Mean ± Ileum 11 12 13 Mean ± a b

Absorption after 2 weeks of ethanol intake

Absorption before ethanol intake H 2O

Na

Cl

K

HC0 3

H 2O

Na

± ± ± ± ±

0.1 0.1 0.06 0.2 0.2

106 171 190 271 185

± ± ± ± ±

18 7 44 15 34

4.5 10.0 4.5 12.0 7.8

± ± ± ± ±

1 2 1 2 2

236 318 90 241 221

± ± ± ± ±

30 35 40 34 48

ND ND ND ND

BE

0.82 1.50 1.30 1.70 1.33

0.28 0.96 0.67 0.28 0.48

± ± ± ± ±

0.1 0.1 0.1 0.1 0.17

± ± ± ± ± ± ±

0.1 0.2 0.2 0.1 0.2 0.05 0.06

130 130 104 124 163 128 130

± ± ± ± ± ± ±

5 24 25 33 32 11 8

5.0 2.3 11.0 6.0 7.0 5.0 6.0

± ± ± ± ± ± ±

1 1 3 1 2 1 1

140 117 94 193 161 166 145

± ± ± ± ± ± ±

23 30 30 40 14 18 15

ND ND ND ND ND ND

BE

1.09 0.78 0.98 0.70 1.04 0.86 0.91

-0.2 -0.71 0.15 0.15 -0.30 0.11 -0.13

± ± ± ± ± ± ±

0.01 0.05 0.06 0.1 0.1 0.03 0.14

BE

1.2 0.65 0.78 0.88

± ± ± ±

0.1 0.06 0.2 0.17

164 113 121 133

± ± ± ±

39 10 29 16

4.0 2.0 3.0 3.0

± ± ± ±

1 1 1 0.6

193 135 133 154

± ± ± ±

14 18 31 20

-0.68 -0.58 -0.46 -0.57

± ± ± ±

0.1 0.1 0.2 0.04

-52 -25 -20 -32

± ± ± ±

7 5 5 10

35 100 80 35 65

15 47 28 18 16

4 7 7 1 5

-34 ± 22 -140±34 29 ± 16 -7 ± 2 -70 ± 20 34 ± 6 -20 ± 29

9 -2 7 2 2

-94 -62 -70 -75

± ± ± ± ±

± ± ± ±

Cl

K

22 31 40 7

HC0 3

± ± ± ± ±

1 1 1 2 1

113 140 134 13 100

± ± ± ± ±

32 18 31 15 30

ND ND ND ND

± ± ± ± ± o± 3 ±

3 2 2 1 1 1 1

-20 -157 46 20 10 60 -7

± ± ± ± ± ± ±

1 50 21 5 25 20 32

ND ND ND ND ND ND

-2 ± 1 -5 ± 1 o± 1 -2.7 ± 7

-51 -58 -100 -89

± ± ± ±

19 20 30 11

-75 -78 -40 -65

± ± ± ±

11 5 12 12

Minus sign indicates secretion; ND, not determined. Diet A, folate supplemented; diet B, folate deficient.

TABLE

4. Effect of 2 weeks of ethanol intake on serum folate levels Study

Preethanol

Postethanol ng/ml

Folate supplemented 1 2 3 4 Mean ± BE Folate deficient 5 6 7 8 9 10 11 12 13 Mean ± BE

5.5 7.5 3.3 4.0 5.1 ± 0.9

12.6 31.0 9.4 15.5 17 ± 4.8

4.9 4.9 5.8 12.7 5.7 5.5

4.6 9.2 5.8 8.3 4.4

5.8 5.4 6.3 ± 0.9

6.8 3.5 6.1 ± 0.8

Effect of chronic intake of ethanol on intestinal transport. Our data clearly indicate that the intake of ethanol for a 2-week period produces either a net reduction in sodium and water absorption or a small net secretion of sodium and water. Although these data do not differentiate between reduction of absorption or stimulation of secretion by the intestine, they offer a possible explanation for the diarrhea that often accompanies chronic alcoholism. More pronounced alterations in water and sodium transport in the subjects put on a folate-deficient diet suggest that folic acid supplementation may reduce some of the deleterious effects of

chronic ethanol intake on the human intestine. Such a relationship has been suggested by others with regard to jejunal glycolytic enzymes and glucose transport. 11,29 In contrast to previous observations 1o,3 our studies do not show a strict correlation between the level of the serum folate levels and the impairment of intestinal transport by chronic ethanol intake. It should be pointed out that in previous studies experiments were carried out in a population of reformed chronic alcoholics who took the experimental diet for a much longer time (6 to 8 weeks), at the end of which the serum folate levels were depressed. The present experiments indicate that the intestinal absorptive abnormalities precede the development of low serum folate levels. The mechanism of the altered sodium transport during the chronic studies remains speculative. Inasmuch as sodium transport in the human jejunum and ileum is an active energy-dependent process, 30, 31 it is tempting to postulate an inhibition of active transport. Na-Kactivated adenosine triphosphatase has been associated with the active transport of sodium in the intestine,32, 33 and ethanol has been shown to reduce Na-K-adenosine triphosphatase levels in the rat cerebral cortex and guinea pig intestinal mucosa. 34 The chronic administration of ethanol, however, does not seem to produce a reduction in adenosine triphosphatase levels in guinea pigs in spite of a reduction in sodium absorption. 35 There are no simultaneous measurements of Na-K-activated adenosine triphosphatase levels and sodium absorption in the human intestine. Furthermore, because measurements of net absorption do not differentiate between reduced absorption or increased secretion, simultaneous measurements of absorptive function and cyclic

June 1977

ETHANOL AND INTESTINAL SODIUM TRANSPORT

nucleotides, incriminated in intestinal scretion,36 may explain more adequately the mechanisms involved in the observed abnormalities of transport. Finally, ultrastructural changes that have been observed in the gastrointestinal tract of rats and man after the ingestion of ethanop7, 38 may contribute to the observed alterations in intestinal transport. It is interesting to note, however, that the abnormalities of transport produced by high concentrations of ethanol seem to persist after the reversion of the intestinal histology to normal, 9 suggesting that more subtle biochemical changes in the epithelial cell may be responsible for the abnormalities of transport. These observations offer one possible explanation for the diarrhea that affects patients with chronic alcoholism. The alterations in water and sodium transport in the jejunum and ileum could also influence the absorption of other nutrients by increasing the thickness of the unstirred water layer.39 The previously observed abnormalities of absorption of other water-soluble substances such as thiamine ,40, 41 folic acid,42 d-xylose, and amino acids,43-45 have not taken into account the effects of ethanol on sodium and water transport and may be in part secondary to changes in sodium and water absorption. REFERENCES 1. Fordtran J: Speculations on the pathogenesis of diarrhea. Fed Proc 26:1405-1414, 1967 2. Mezey E: Intestinal function in chronic alcoholism. Ann NY Acad Sci 252:215-227, 1975 3. Krasner N, Cochran KM, Russell RI, et al: Alcohol and absorption from the small intestine. Gut 17:245-248, 1976 4. Israel Y, Kalant H: Effect of ethanol on the transport of sodium in frog skin. Nature 200:476-478, 1963 5. Smith BM, Skillman JJ, Edwards BG, et al: Permeability of the human gastric mucosa: alterations by acetylsalicyclic acid and ethanol. N Engl J Med 285:716-721, 1971 6. Geall MG, Phillips SF, Summerskill WHJ: Profile of gastric potential difference in man: effects of aspirin, alcohol, bile, and endogenous acid. Gastroenterology 58:437-443, 1970 7. Dinda PK, Beck IT, Beck M, et al: Effect of ethanol on sodiumdependent glucose transport in the small intestine of the hamster. Gastroenterology 68:1517-1526, 1975 8. Beck IT, Dinda PK, Beck M: Osmotic changes of the fluid transported across the jejunum in the presence of ethanol in the luminal content (abstr). Gastroenterology 64:877, 1973 9. Fox JE, McElligott TF, Beck IT: The effect of ethanol on jejunal glucose and water transport and morphology in the hamster in vivo (abstr). Gastroenterology 70:884, 1976 10. Greene HL, Herman RH, Kraemer S: Stimulation of jejunal adenyl cyclase by ethanol. J Lab Clin Med 78:336-342, 1971 11. Halsted CH, Robles EA, Mezey E: Intestinal absorption in folatedeficient alcoholics. Gastroenterology 64:526-532, 1973 12. Fordtran JS: Marker perfusion techniques for measuring intestinal absorption in man. Gastroenterology 51:1089-1094, 1966 13. Whalen GE, Harris JA, Soergel KH: Sodium and water absorption from the human small intestine: the accuracy of the perfusion method. Gastroenterology 49:975-984, 1965 14. Visscher MB, Fetcher ES Jr, Carr CW: Isotopic tracer studies on the movement of water and ions between intestinal lumen and blood. Am J PhysioI142:550-575, 1944 15. Lieber CS, Jones DP, DeCarIe LM: Effects of prolonged ethanol intake: production of fatty liver despite adequate diet. J Clin

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Invest 44:1009-1021, 1965 16. Herbert V: A palatable diet for producing experimental folate deficiency in man. Am J Clin Nutr 12:17-20, 1963 17. Hyden S: A turbidometric method for the determination of higher polyethylene glycols in biological materials. Lantbrukshogsk Ann 22:139-145, 1956 18. Jain NC: Direct blood-injection method for gas chromatographic determination of alcohols and other volatile compounds. Clin Chern 17:82-85, 1971 19. Herbert V: Aseptic addition method for Lactobacillus casei assay of folate activity in human serum. J Clin PathoI19:12-16, 1966 20. Snedecor GW, Cochran G: Statistical Methods. Sixth edition. Ames. Iowa, The Iowa State University Press, 1968, p 91-119 21. Turnberg L, Fordtran JS, Carter NW et al: Mechanism ofbicarbonate absorption and its relationship to sodium transport in the human jejunum. J Clin Invest 49:548-556, 1970 22. Phillips SF, Summerskill WHJ: Water and electrolyte transport during maintenance of isotonicity in human jejunum and ileum. J Lab Clin Med 70:686~98, 1967 23. Lieber CS: Hepatic and metobolic effects of alcohol (1966 to 1973). Gastroenterology 65:821-846, 1973 24. Parsons DS, Wingate DL: The effect of osmotic gradients on fluid transfer cross rat intestine in vitro. Biochim Biophys Acta 46:170-183, 1961 25. Annegers JH, Wakefield H: Electrolyte, urea and water movements across canine intestinal mucosa. Am J Physiol 203:563566, 1962 26. Curran PF: Na, CI, and water transport by rat ileum in vitro. J Gen PhYGiol 43:1137-1148, 1960 27. Fordtran JS, Dietschy JM: Water and electrolye movement in the intestine. Gastroenterology 50:263-285, 1966 28. Wright EM, Daimond JM: Patterns of non-electrolyte permeability. Proc R Soc Lond [Bioi] 172:227-271, 1969 29. Greene HL, Stifel FB, Herman RH, et al: Ethanol-induced inhibition of human intestinal enzyme activities: reversal by folic acid. Gastroenterology 67:434-440, 1974 30. Fordtran JS, Rector FC, Carter NW: The mechanism of sodium absorption in the human small intestine. J Clin Invest 47:884900, 1968 31. Turnberg LA, BieberdorfFA, Morawski SE, et al: Interrelationships of chloride, bicarbonate, sodium and hydrogen transport in the human ileum. J Clin Invest 49:557-567, 1970 32. Katz AI, Epstein FH: Physiologic rate of Na-K-ATP-ase in the transport of cations across biological membranes. N Engl J Med 278:253-261, 1968 33. Charney AN, Kinsey MD, Myers L, et al: Na+-K+-Activated adenosine triphosphatase and intestinal electrolyte transport. Effect of adrenal steroids. J Clin Invest 46:653-660, 1975 34. Carter EA, Isselbacher KJ: Effect of ethanol on intestinal adenosine triphosphate (ATP) content. Proc Soc Exp BioI Med 142:1171-1173, 1973 35. Kraster N, Carmichael HA, Russell RI, et al: Alcohol and absorption from the small intestine. Gut 17:249-251, 1976 36. Kimberg DV: Cyclic nucleotides and their role in gastrointestinal secretion. Gastroenterology 67:1023-1064, 1974 37. Rubin E, Rybak BJ, Lindebaum CD, et al: Ultrastructural changes in the small intestine induced by ethanol. Gastroenterology 63:801-814, 1972 38. Baraona E, Pirola RC, Lieber C: Small intestinal damage and changes in cell population produced by ethanol ingestion in the rat. Gastroenterology 66:226-234, 1974 39. Dietschy JM, Westergaard H: The effect of unstirred water layers at various transport processes in the intestine. In Intestinal Absorption and Malabsorption. Edited by TZ Csaky. New York, Raven Press, p 197-207, 1975 40. Thompson AL, Baker H, Leevy CM: Patterns of a5S-thiamine hydrochloride absorption in the malnourished alcoholic patient.

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J Lab Clin Med 76:34-35, 1970 41. Tomasulo PA, Kater RMH, Iber FL: Impairment of thiamine absorption in alcoholism. Am J Clin Nutr 21:1340-1344, 1968 42. Halsted CH, Robles EA, Mezey E: Decreased jejunal uptake of labelled folic acid in alcoholic patients: roles of alcohol and nutrition. N Engl J Med 285:701-706, 1971 43. Lindenbaum J , Lieber CS: Effect of chronic ethanol administra-

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tion on intestinal absorption in man in the absence of nutritional deficiency. Ann NY Acad Sci 252:228-234, 1975 44. Chang T, Lewis J , Glazko AJ: Effect of ethanol and other alcohols on the transport of amino acids and glucose by everted sacs of rat small intestine. Biochim Biophys Acta 135:1000-1007, 1967 45. Israel Y, Valenzuela JE, Salazar I, et al: Alcohol and amino acid transport in the human small intestine. J Nutr 98:222-224, 1969